The expression and function of Epstein-Barr virus encoded latent genes

Abstract

The association of Epstein-Barr virus (EBV) with various malignancies is well established but the pattern of EBV latent gene expression in these different tumours is variable, reflecting distinct aspects of the virus-cell interaction. These different forms of EBV latency are associated with phenotypic variation and highlight the influence of EBV latent proteins on cell growth and survival. The EBV latent proteins have distinct functions associated with the maintenance of EBV infection and the control of various signalling and transcriptional pathways that facilitate the proliferation and survival of infected cells. Understanding the function of these EBV latent proteins will not only provide insight into the mechanisms governing fundamental cell processes but will also identify targets for novel treatment.

Figure 1

Location of open reading frames for the Epstein-Barr virus (EBV) latent proteins on the BamHI restriction map of the prototype B95.8 EBV genome. The BamHI fragments are named according to size, with A being the largest. Note that the latent membrane protein 2 (LMP2) proteins are produced from mRNAs that splice across the terminal repeats (TR) in the circularised EBV genome. EBNA, EBV encoded nuclear antigen.

Figure 2

Location and transcription of the Epstein-Barr virus (EBV) latent genes on the double stranded viral DNA episome. The large solid arrows represent coding exons for each of the latent proteins and the direction in which they are transcribed. EBNA-LP is transcribed from variable numbers of repetitive exons in the BamHI W fragments. Latent membrane protein 2 (LMP2) is composed of multiple exons located either side of the terminal repeat (TR) region, which is formed during the circularisation of the linear DNA to produce the viral episome. The open arrows represent the highly transcribed non-polyadenylated RNAs, EBER1 and EBER2, which are a consistent feature of latent EBV infection. The outer long arrowed line represents EBV transcription in latency type III, where all the EBNAs are transcribed from either the Cp or Wp promoter; the different EBNAs are encoded by individual mRNAs generated by differential splicing of the same long primary transcript. The inner shorter arrowed line represents the EBNA1 transcript originating from the Qp promoter located in the BamHI Q region; this is transcribed in latency types I and II. EBNA, EBV encoded nuclear antigen; LP, leader proteins.

Figure 3

Epstein-Barr virus (EBV) gene transcription in the three forms of latency. The top panel shows the position of the exons on a linear map of the genome. The lower panels show the direction of transcription from each promoter (arrows) and the splicing structure between the exons. Coding exons are shown in black and non-coding exons in white. EBER, EBV encoded small RNA; EBNA, EBV encoded nuclear antigen; LP, leader protein; LMP, latent membrane protein; TR, terminal repeat.

Figure 4

Schematic representation of the known signalling pathways activated by Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1). The LMP1 cytoplasmic tail contains two functional domains with respect to NF-κB activation (shown as white boxes). The extreme C-terminal domain (CTAR2, aa 352–386) binds TRADD and RIP and is the major mediator of NF-κB, JNK, and p38 signalling in most cell lines. TRAF2, a TRADD interacting protein, regulates CTAR2 induced NF-κB activation via a NIK→IKK→IκBα cascade, but the components of JNK and p38 signalling downstream of TRADD/TRAF2 remain largely unknown. The membrane proximal region (CTAR1, aa 187–231), which is crucial for B cell transformation, interacts weakly with TRAF2 and induces only low amounts of NF-κB and p38 activation. TRAF1 and TRAF3 also bind CTAR1 and might influence TRAF2 mediated signals. The intermediate region between CTAR1 and CTAR2 has been shown to bind JAK3 and activate STAT signalling, whereas the transmembrane domains of LMP1 mediate activation of the small GTPase, Cdc42, leading to cytoskeletal changes. CTAR, C-terminal activating region; IKK, IκB kinase; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen activated protein kinase; NIK, MAPK kinase kinase; RIP, receptor interacting protein; SEK, extracellular signal related kinase (ERK) kinase; STAT, signal transducers and activators of transcription; TRADD, tumour necrosis factor receptor associated death domain; TRAF, tumour necrosis factor receptor associated factor.